Sorted By Test Name - Mayo Medical Laboratories

VHLKP
89084
Interpretation: All detected alterations will be evaluated according to American College of Medical
Genetics and Genomics (ACMG) recommendations.(1) Variants will be classified based on known,
predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or
known significance.
Reference Values:
An interpretive report will be provided.
Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for
standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med
2008:10(4):294-300 2. Online Mendelian inheritance in Man-OMIM. Available from URL:
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=193300 3. Universal Mutation
database-UMD-VHL mutations database page. Available from URL: http://www.umd.be:2020/ 4. Maher
ER, Kaelin WG Jr: von Hippel-Lindau disease (Reviews in Molecular Medicine). Medicine
1997;76:381-391 5. Pack SD, Zbar B, Pak E, et al: Constitutional von Hippel-Lindau (VHL) gene
deletions detected in VHL families by fluorescence in situ hybridization. Cancer Res 1999;59:5560-5564
6. Richards FM: Molecular pathology of von Hippel-Lindau disease and the VHL tumor suppressor gene.
Expert Rev Mol Med 2001;3:1-27 7. Hes FJ, Hoppener JWM, Lips CJM: Clinical review 155:
pheochromocytoma in von Hippel-Lindau disease. J Clin Endocrinol Metab 2003;88:969-974 8. Ong KR,
Woodward ER, Killick P, et al: Genotype-phenotype correlations in von Hippel-Lindau disease. Hum
Mutat 2007;28:143-149
Von Hippel-Lindau (VHL) Gene, Known Mutation
Clinical Information: von Hippel-Lindau (VHL) disease is an autosomal dominant cancer syndrome
with a birth incidence of approximately 1:36,000 livebirths. It predisposes affected individuals to the
development of mainly 5 different types of neoplasms: retinal angioma (>90% penetrance), cerebellar
hemangioblastoma (CHB, >80% penetrance), clear-cell renal cell carcinoma (cRCC, approximately 75%
penetrance), spinal hemangioblastoma (SHB, approximately 50% penetrance), and pheochromocytoma
(PC, approximately 30% penetrance). Angiomas in other organs, pancreatic cysts/adenomas/carcinomas,
islet cell tumors, and endolymphatic sac tumors can also occur, but at much lesser frequencies.
VHL-related tumors start presenting at approximately 10 to 15 years of age (retinal angioma might
present earlier), except for cRCC, which lags about a decade behind. For each tumor type, the incidence
rates rise steadily, albeit at different slopes, throughout life. VHL disease is caused by germline
loss-of-function point mutations, deletions or insertions (approximately 80% of cases), or large germline
deletions (approximately 20% of cases) of 1 copy of the VHL gene. Approximately 20% of cases are due
to new mutations. VHL codes for a protein that is involved in ubiquitination and degradation of a variety
of other proteins, most notably hypoxia-inducible factor (HIF). HIF induces expression of genes that
promote cell survival and angiogenesis under conditions of hypoxia. It is believed that diminished HIF
degradation due to inactive VHL protein causes the tumors in VHL disease. Tumors form when the
remaining intact copy of VHL is somatically inactivated in target tissues. Sporadic cRCC, unrelated to
VHL disease, also shows somatic deletions, mutations, or aberrant methylation in 80% to 100% of cases.
Retinal angioma, CHB, and SHB cause morbidity, and some mortality, through pressure on adjacent
structures and through retinal or subarachnoid hemorrhages. VHL-related cRCC and PC follow a similar
clinical course as their sporadic counterparts, with substantial morbidity and mortality. Early detection of
VHL-related tumors can reduce these adverse outcomes, and surveillance of affected individuals is
therefore widely advocated. Genetic testing is the most accurate way to identify presymptomatic
individuals, who can then be entered into a surveillance program. Genetic testing might also predict the
types of tumors that will occur, and can, therefore, be used to individualize surveillance programs. Certain
combinations of the 5 major VHL-tumors cluster in VHL families. This observation has led to a
phenotype-based classification of VHL syndrome into type 1 (cRCC with any combination of retinal
angioma, CHB, or SHB), type 2A (PC with any combination of retinal angioma, CHB, or SHB), type 2B
(both cRCC and PC with any combination of retinal angioma, CHB, or SHB) and type 2C (isolated PC).
Type 1 accounts for 60% to 80% of cases, while type 2C is exceedingly rare. However, phenotyping is
only accurate in large kindreds. In smaller kindreds, genetic testing can assist in tailoring follow-up to
patient needs. For example, missense mutations, particularly those affecting surface amino acids involved
in maintaining the surface structural integrity of VHL protein, are strongly associated with PC. By
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